Aromatic polyenic compounds and pharmaceutical/cosmetic compositions comprised thereof

ABSTRACT

Novel pharmaceutically/cosmetically-active aromatic polyenic compounds have the structural formula (I):and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular, bone and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

CROSS-REFERENCE TO COMPANION APPLICATIONS

CopendingThis is a reissue application of U.S. Pat. No. 5,705,167. Theapplication on which the '167 patent is based relates to copendingapplications Ser. No. 08/429,096 pending (now U.S. Pat. No. 5,766,610 )[Attorney Docket No. 016800-023] and Ser. No. 08/429,045 (now U.S. Pat.No. 5,574,036 ) [Attorney Docket No. 016800-025], both filedconcurrently herewith and assigned to the assignee hereof. Cf. copendingapplications Ser. No. 08/356,913 pending (now U.S. Pat. No. 5,723,499 )[Attorney docket No. 016800-006], Ser. No. 08/357,024 pending (now U.S.Pat. No. 5,716,624 ) [Attorney Docket No. 016800-007 ] and Ser. No.08/356,680 pending (now U.S. Pat. No. 5,709,867 ) [Attorney Docket No.016800-008], each filed Dec. 15, 1994 and each also assigned to theassignee hereof.

BACKGROUND OF THE INVENTION

Technical Field of the Invention

The present invention relates to novel aromatic polyenic compounds andto pharmaceutical/cosmetic compositions comprised thereof; the subjectcompounds are especially useful in humans or veterinary medicine, or,alternatively, in cosmetic compositions.

SUMMARY OF THE INVENTION

The compounds according to the invention display a pronounced activityin the fields of cell differentiation and proliferation, and areparticularly useful in the topical and systemic treatment ofdermatological conditions associated with a keratinization disorder,dermatological (or other) conditions including an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. The subject compounds can, in addition, beused for the treatment of the degenerative diseases of the connectivetissue, for combating aging of the skin, whether photoinduced orchronologic, and for treating cicatrization or healing disorders. Theyare also useful for ophthalmological applications, especially for thetreatment of corneopathies.

The compounds according of this invention are also useful for thetreatment of osteoporosis or for the treatment of viral diseases, aswell as for the treatment of any disease state associated withhypervitaminosis A. Generally, they are useful for the treatment of anydisease or condition associated with a modification in the expression ofreceptors belonging to the superfamily of steroid and thyroid hormonereceptors.

Too, the compounds according to this invention can also be formulatedinto cosmetic compositions for body and hair care/hygiene.

Briefly, the aromatic polyenic compounds according to the invention havethe following structural formula (I):

in which R₁ is a —CH₃ radical, a radical —CH₂—O—R₉, a radical—CH₂—O—CO—R₁₀, or a radical —CO—R₁₁, wherein R₉, R₁₀ and R₁₁ are asdefined below; R₂ is a hydrogen atom or a lower alkyl radical; R₃ is ahydrogen atom or a lower alkyl radical; R₄ is a hydrogen atom; R₅ is ahydrogen atom or a lower alkyl radical; R₆ is a hydrogen atom, a linearor branched alkyl radical having from 1 to 20 carbon atoms, a radical—O—CH₂—O—CH₂—CH₂—O—CH₃ or a radical —O—R₁₃, wherein R₁₃ is as definedbelow; R₇ and R₈ independently are each (i) a hydrogen atom, (ii) alinear or branched alkyl radical having from 1 to 20 carbon atoms, (iii)a cycloaliphatic radical, (iv) a radical —O—CH₂—O—CH₂—CH₂—O—CH₃, (v) aradical —O—R₁₃, or (vi) a radical —S(O)_(n)R₁₃, wherein R₁₃ and n are asdefined below, with the proviso that R₄ and R₆ may together form, withthe carbon atoms from which they depend and with the adjacent benzenering, a naphthalene ring, and at least one of R₇ and R₈ has the abovedefinition (ii) or (iii); R₉ is a hydrogen atom or a lower alkylradical; R₁₀ is a lower alkyl radical R₁₁ is (a) a hydrogen atom, (b) alower alkyl radical, (c) a radical of formula:

in which R′ and R″ independently are each a hydrogen atom, a lower alkylradical, a mono- or polyhydroxyalkyl radical, an optionally substitutedaryl radical, or an amino acid residue or peptide residue or sugarresidue, with the proviso that R′ and R″ may together form, with thenitrogen atom from which they depend, a nitrogen-containing heterocycle,or (d) a radical —OR₁₂, wherein R₁₂ is a hydrogen atom, a linear orbranched alkyl radical having from 1 to 20 carbon atoms, an alkenylradical, a mono- or polyhydroxyalkyl radical, an optionally substitutedaryl or aralkyl radical, or a sugar residue, or an amino acid residue orpeptide residue; R₁₃ is a hydrogen atom or a linear or branched alkylradical having from 1 to 20 carbon atoms; and n is an integer equal to0, 1 or 2.

This invention also features the salts of the compounds of formula (I)in the event that the radical R₁ represents a carboxylic acid function,or when R₇ and/or R₈ represents a sulfonic acid function, as well as theoptical (chiral) and geometric isomers thereof. When the compoundsaccording to the invention exist in the form of salts, they arepreferably alkali metal salts or alkaline earth metal salts, or,alternatively, zinc salts or salts of an organic amine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 set forth the reaction schemes/mechanisms illustratingrepresentative syntheses for the preparation of the aromatic polyeniccompounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THEINVENTION

More particularly according to the present invention, by the term “loweralkyl radical” is intended an alkyl radical having from 1 to 6 carbonatoms, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl andhexyl radicals.

By the term “linear or branched alkyl radical having from 1 to 20 carbonatoms” is preferably intended methyl, ethyl, propyl, 2-ethylhexyl,octyl, dodecyl, hexadecyl and octadecyl radicals.

By the term “cycloaliphatic radical” is intended a mono- or polycyclicradical such as, for example, the 1-methylcyclohexyl radical or the1-adamantyl radical.

By the term “monohydroxyalkyl radical” is intended a radical preferablyhaving 2 or 3 carbon atoms, in particular a 2-hydroxyethyl,2-hydroxypropyl or 3-hydroxypropyl radical.

By the term “polyhydroxyalkyl radical” is intended a radical preferablyhaving from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such asthe 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.

By the term “aryl radical” is preferably intended a phenyl radical whichis optionally substituted by at least one halogen atom, or a hydroxyl ornitro functional group.

By the term “aralkyl radical” is preferably intended a benzyl orphenethyl radical optionally substituted by at least one halogen atom,or a hydroxyl or nitro functional group.

By the term “alkenyl radical” is intended a radical preferably havingfrom 2 to 5 carbon atoms and one or more sites of ethylenicunsaturations, such as, more particularly, the allyl radical.

By the term “sugar residue” is intended a residue derived in particularfrom glucose, from galactose of from mannose, or alternatively fromglucuronic acid.

By the term “amino acid residue” is particularly intended a residuederived from lysine, from glycine or from aspartic acid, and by the term“peptide residue” is more particularly intended a dipeptide ortripeptide residue prepared via the combination of amino acids.

Lastly, by the term “heterocycle” is preferably intended a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted inthe 4-position by a C₁-C₆ alkyl radical or a mono- or polyhydroxyalkylradical as defined above.

Among the compounds of formula (I) according to the present invention,particularly representative are the following:

trans-7-[3-(1-Adamantyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

Ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate;

trans-7-[3-(1-Adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

(2Z,4E,6E)-7-[3-(1-Adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

trans-5-[-7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;

trans-5-[-7-(1-Adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;

trans-5-[-7-(1-Adamantyl)-6-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;

trans-5-[-7-(1-Adamantyl)-6-propyloxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;

trans-7-[3-(1-Methylcyclohexyl)-4-hydroxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

(2Z,4E,6E)-7-[3-(1-Methylcyclohexyl)-4methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

trans-7-[3-(1-Adamantyl)-4-isopropyloxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

trans-7-[3-(1-Adamantyl)-4-methoxyethoxymethoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;

trans-7-[3-(1-Adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoicacid;

trans-7-[3-(1-Adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrien-1-ol;

trans-7-[3-(1-Adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrien-1-al;

trans-N-Ethyl-7-[3-(1-adamantyl)-4-methoxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienecarboxamide;

trans-N-4-Hydroxyphenyl-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienecarboxamide;

trans-7-(3-tert-Butyl-4-methoxyethoxymethoxy-phenyl)-3,7-dimethyl-2,4,6-heptatrienoicacid;

Ethyltrans-7-(3-tert-butyl-4-hydroxphenyl)-3,7-dimethyl-2,4,6-heptatrienoate;

Ethyltrans-7-(3-tert-butyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoate;

Ethyltrans-7-[4-(1-adamantyl)-3-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate.

According to the present invention, the more particularly preferredcompounds of formula (I) are those in which at least one, and preferablyall, of the conditions given below are satisfied:

R₁ is a radical —CO—R₁₁;

R₇ is the adamantyl radical;

R₄ is a hydrogen atom;

R₆ is a hydrogen atom or a linear or branched alkyl radical having from1 to 20 carbon atoms; and

R₄ and R₆ together form, with the adjacent benzene ring, a naphthalenering:

The present invention also features the processes for the preparation ofthe compounds of formula (I), in particular via the reaction schemesillustrated in FIGS. 1 and 2.

Thus the compounds of formula I(a) may be obtained according to tworoutes (cf. FIG. 1):

(i) either according to the synthesis described by M. Julia and D.Arnould, in Bull. Soc. Chim., 746 (1973). Hence, by reacting anacetophenone derivative (1) with a vinylmagnesium bromide, theα-hydroxyvinyl (2) is prepared, which is then reacted with sodiumphenylsulfinate in order to obtain the compound (3). The anion of thederivative (3) is formed in the presence of a base, for examplepotassium tert-butoxide, and reacts with an ethyl γ-bromosenecionate toobtain the sulfone ester (4). Removal of the sulfone group is carriedout in the presence of a base, for example potassium tert-butoxide orDBU, and, after saponification of the ester function in alcoholic sodiumhydroxide or potassium hydroxide, the acid I(a) is ultimately obtained.

(ii) or by reaction of the acetophenone (1), according to a Horner-typereaction, with a C2-phosphononitrile, in order to prepare thepropenenitrile derivative (5). After partial reduction withdiisobutylaluminium hydride (DIBAH), the propenal derivative (6) isobtained. Treatment of this aldehyde with the lithio derivative of aphosphonate ester results in the formation of the ester (7) which, onsaponification in alcoholic sodium hydroxide or potassium hydroxide,ultimately gives the acid I(a).

The compounds of formula I(b) and I(c) may themselves be prepared asfollows (cf. FIG. 2):

(i) either from the aldehyde (1) by reduction in the presence of analkali metal hydride, such as sodium borohydride or lithium aluminumhydride. The alcohol (2) thus obtained is then converted into thephosphonium salt (3) by reaction with (C₆H₅)₃P.HBr in methanol, thiscompound (3) then being converted into the ester of formula I(b) by theaction of the lithio or sodio derivative of a phosphonate ester;

(ii) or from the aldehyde (1) according to a sequence of two Horner-typereactions. First, the compound (1) is reacted with dimethyl2-oxopropylphosphonate in the presence of DBU in THF to obtain theketone (4), and the latter is then converted into the ester derivativeI(b) by reaction with the lithio or sodio derivative of a phosphonateester. On saponification of the ester I(b) in the presence of alcoholicsodium hydroxide or potassium hydroxide, the acid I(c) is ultimatelyobtained.

Where R₆, R₇ and R₈ represent the hydroxyl radical, the compounds offormula (I) are advantageously prepared by protecting the phenolfunction, preferably in the tert-butyldimethylsilyloxy ormethoxyethoxymethoxy form, the deprotection then being carried outeither in the presence of tetrabutyl-ammonium fluoride or trimethylsilyliodide, or in acidic medium (HCl).

The present invention also features therapeutic/pharmaceuticalapplications of the compounds of formula (I).

These compounds exhibit antagonistic activity with respect to theexpression of one or more biological labels (markers) in the test fordifferentiation of mouse embryonic teratocarcinoma cells (F9)(SkinPharmacol., 3, pp. 256-267 (1990) and/or for the differentiation ofhuman keratinocytes in vitro (Anal. Biochem., 193, pp. 232-236 (1991)).They may also exhibit a specific agonistic activity with respect tocertain receptors, and antagonistic activities with respect to others.

The compounds according to the invention are particularly suitable inthe following fields of therapy:

(1) for treating dermatological conditions associated with akeratinization disorder related to differentiation and proliferation, inparticular for treating simple acne, comedones, polymorphonuclearleucocytes, rosacea, nodulocystic acne, severe cystic acne, senile acneand secondary acnes such as solar, medication-related or occupationalacne,

(2) for treating other types of keratinization disorders, in particularichthyosis, ichthyosiform states, Darier's disease, palmoplantarkeratoderma, leucoplasias and leucoplasiform states, and cutaneous ormucous (buccal)lichen,

(3) for treating other dermatological conditions associated with akeratinization disorder manifesting an inflammatory and/orimmunoallergic component and, in particular, all forms of psoriasis,whether cutaneous, mucous or ungual, and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds may also be used fortreating inflammatory conditions not exhibiting keratinization disorder,

(4) for treating all dermal or epidermal proliferations, whether benignor malignant, and whether or not of viral origin or otherwise, such ascommon warts, flat warts and verruciform epidermodysplasia, oral orflorid papillomatoses and the proliferations which can be induced byultraviolet radiation, in particular in the case of basocellular andspinocellular epithelioma,

(5) for treating other dermatological disorders, such as bullosis andcollagen diseases,

(6) for treating certain ophthalmological disorders, especiallycorneopathies,

(7) for repairing or combating aging of the skin, whether photoinducedor chronologic, or for reducing actinic keratoses and pigmentations, orany pathologies associated with chronological or actinic aging,

(8) for preventing or curing the stigmata of epidermal and/or dermalatrophy induced by local or systemic corticosteroids, or any other formof cutaneous atrophy,

(9) for preventing or treating cicatrization or healing disorders or forpreventing or repairing vibices and stretch marks,

(10) for combating disorders of sebaceous functioning, such as thehyperseborrhoea of acne or simple seborrhoea,

(11) for the treatment or prevention of cancerous or precancerousstates,

(12) for the treatment of inflammatory conditions such as arthritis,

(13) for the treatment of any skin or general disease state of viralorigin,

(14) for the prevention or treatment of alopecia,

(15) for the treatment of dermatological or general conditions includingan immunological component,

(16) for the treatment of ailments of the cardiovascular system, such asarteriosclerosis,

(17) for the treatment or prevention of osteoporosis.

For the aforesaid therapeutic or pharmaceutical applications, thecompounds according to the invention may advantageously be used incombination with other bioactive compounds, for example with the Dvitamins or derivatives thereof, with corticosteroids, withanti-free-radical agents, with α-hydroxy or α-keto acids or derivativesthereof, or alternatively with ion-channel blockers. By the term “Dvitamins or derivatives thereof” are intended, for example, derivativesof vitamin D₂ or D₃ and in particular 1,25-dihydroxyvitamin D₃. By theterm “anti-free-radical agents” are intended, for example, α-tocopherol,superoxide dismutase, ubiquinol or certain metal-chelating agents. Bythe term “α-hydroxy or α-keto acids or derivatives thereof” areintended, for example, lactic acid, malic acid, citric acid, glycolicacid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid orthe salts, amides or esters thereof. By the term “on-channel blockers”are intended, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine3-oxide) and derivatives thereof.

The present invention thus also features medicinal compositionscontaining at least one compound of formula (I), one of the optical orgeometric isomers thereof, or one of the salts or other derivativesthereof.

The pharmaceutical/therapeutic compositions of the present invention,intended in particular for the treatment of the aforesaid disease statescomprise a pharmaceutically acceptable vehicle, carrier or diluent whichis compatible with the mode or regime of administration selected for thegiven composition, at least one compound of formula (I), one of theoptical or geometrical isomers thereof, or one of the salts, etc.,thereof.

The compounds according to the invention may be administered via thesystemic, enteral, parenteral, topical or ocular route.

Via the enteral route, the medicinal/pharmaceutical compositions may bein the form of tablets, gelatin capsules, dragees, syrups, suspensions,solutions, elixirs, powders, granules, emulsions, microspheres ornanospheres or lipidic or polymeric vesicles which permit controlledrelease. Via the parenteral route, the compositions may be in the formof solutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administered at adaily dose of approximately 0.01 mg/kg to 100 mg/kg of body weight, andthis at the rate or regime of in 1 to 3 doses per diem.

Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucosae and may then be in the form ofpasty ointments, creams, milks, creamy ointments, powders, impregnatedpads, solutions, gels, sprays, lotions or suspensions. They may also bein the form of microspheres or nanospheres or lipidic or polymericvesicles or polymeric patches and hydrogels which permit controlledrelease. These topical-route compositions may furthermore be either inanhydrous form or in an aqueous form, depending on the particularclinical indication. Via the ocular route, they are principally eyedrops.

These compositions for topical or ocular application contain at leastone compound of formula (I), or one of the optical or geometricalisomers thereof, or, alternatively, one of the salts, etc., thereof, ata concentration preferably ranging from 0.001% to 5% by weight relativeto the total weight of the composition.

The compounds of formula (I) according to the invention also findapplication in the cosmetic field, in particular for body and haircare/hygiene, and especially for treating skin-types with a tendencytowards acne, for promoting the regrowth of the hair, for combating hairloss, for controlling the greasy appearance of the skin or of the hair,for protection against the deleterious effects of the sun or for thetreatment of physiologically dry skin-types, and for preventing and/orcombating photoinduced or chronologic aging.

For cosmetic applications, the compounds according to the invention may,furthermore, be advantageously employed in combination with othercompounds displaying retinoid-type activity, with the D vitamins orderivatives thereof, with corticosteroids, with anti-free-radicalagents, with α-hydroxy or α-keto acids or derivatives thereof, or,alternatively, with ion-channel blockers, all of these various activeagents being as defined above.

The present invention therefore also features cosmetic compositionscomprising a cosmetically acceptable vehicle, carrier or diluentsuitable for topical application, at least one compound of formula (I),or one of the optical or geometrical isomers thereof or one of the saltsthereof, etc. Such cosmetic compositions are advantageously in the formof a cream, a milk, a lotion, a gel, lipidic or polymeric microspheresor nanospheres or vesicles, a soap or a shampoo.

The concentration of the compound of formula (I) in the cosmeticcompositions according to the invention advantageously ranges from 0.01%to 3% by weight relative to the total weight of the composition.

The medicinal and cosmetic compositions according to the invention mayadditionally contain inert additives or even pharmacodynamically orcosmetically active additives or combinations of these additives, andespecially: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; hydrating ormoisturizing agents such as glycerol, PEG 400, thiamorpholine andderivatives thereof or alternatively urea; anti-seborrhoeic agents oranti-acne agents such as S-carboxymethylcysteine and S-benzylcysteamineand the salts or derivatives thereof, or benzoyl peroxide; antibioticssuch as erythromycin and the esters thereof, neomycin, clindamycin andthe esters thereof, and tetracyclines; anti-fungal agents such asketoconazole or 4,5-polymethylene-3-isothiazolidones; agents promotingthe regrowth of the hair, such as Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof,diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andphenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidalanti-inflammatory agents; carotenoids and, in particular, β-carotene;anti-psoriatic agents such as anthraline and derivatives thereof; and,lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoicacid, and the esters and amides thereof.

The compositions according to the invention may also containflavor-enhancing agents, preservatives such as para-hydroxybenzoic acidesters, stabilizing agents, moisture regulator, pH regulators, osmoticpressure modifiers, emulsifying agents, UV-A and UV-B screening agents,and antioxidants such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 Preparation oftrans-7-[3-(1-adamantyl)-4-hydroxypylhen]-3,7-dimethyl-2,4,6-heptatrienoicacid

(a) Syntheses of2-[3-(1-adamantyl)-4-tert-butyldimethylsilyloxy-phenyl]-3-buten-2-ol:

385 mg (1 mmol) of3-(1-adamantyl)-4-tert-butyldimethylsilyloxyacetophenone and 20 ml ofTHF were introduced into a three-necked flask, followed by dropwiseaddition of 1.1 ml (1.1 mmol) or vinyl-magnesium bromide solution (1M)such that the temperature of the reaction medium did not exceed 20° C.The mixture was then stirred at room temperature for one hour and thereaction medium was poured into an ice/water mixture and extracted withethyl ether, and the organic phase was separated out after settling ofthe phases had occurred, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl ether and hexane (15/85). 380 mgof the expected alcohol were thus collected (yield: 92%) in the form ofan oil.

(b) Synthesis of3-[3-(1-adamantyl)-4-tert-butyldimethylsilyloxy-phenyl]-2-butenesulfonylbenzene:

5.9 g (35.8 mmol) of sodium benzenesulfinate, 8 ml of water and 12 ml ofacetic acid were introduced into a round-bottomed flask. The mixture washeated to 60° C. and 7.37 g (17.8 mmol) of the alcohol derivativeobtained above were then added over 15 minutes, and this temperature wasmaintained for four hours. The reaction medium thus obtained was pouredinto water and extracted with hexane, and the organic phase wasseparated out after settling of the phases had taken place, washed withwater, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and hexane (10/90). Afterevaporation of the solvents, 3.1 g of the expected compound werecollected (yield: 32%).

(c) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-tert-butyldimethylsilyloxyphenyl]-5-benzenesulfonyl-3,7-dimethyl-2,6-heptadienoate:

765 mg (6.8 mmol) of potassium tert-butoxide and 5 ml of a solutioncomprising a mixture of THF and N-methylpyrrolidine (5:1) wee introducedinto a round-bottomed flask. While cooling the mixture thus obtained to−65° C. there wee added, successively and dropwise, firstly a firstsolution consisting of 3 g (5.68 mmol) of the derivative obtained instep (b) diluted in 2.5 ml of a [THF/N-methylpyrrolidine] mixture whichwas identical to that indicated above, followed by a second solution of1.3 g (6.25 mmol) of ethyl γ-bromosenecionate diluted in 1 ml of THF andthe entire contents were stirred for one hour at −65° C.

25 ml of ethyl ether were then added, the temperature permitted toincrease to 0° C., 35 ml of water were added and the mixture wasextracted with ethyl ether. The organic phase was separated out aftersettling of the phases had taken place, dried over magnesium sulfate andthen evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and hexane (15/85). Afterevaporation, 4 g of the expected ester were collected (yield: 100%) inthe form of a colorless oil.

(d) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate:

4 g (6.25 mmol) of the above ester obtained in step (c) and 40 ml of THFwere introduced into a round-bottomed flask under a stream of nitrogen,the mixture was cooled to −30° C. and 700 mg (6.25 mmol) of potassiumtert-butoxide were added. The mixture was stirred at this sametemperature for one hour, the temperature was permitted to increase toroom temperature, and the reaction medium was neutralized and extractedwith ethyl ether. The organic phase was separated out after settling ofthe phases had taken place, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and hexane (20/80). Afterevaporation of the solvents, 863 mg of ethyl7-[3-(1-adamantyl)-4-hydroxphenyl]-3,7-dimethyl-2,4,6-heptatrienoatewere collected (yield: 34%) in the form of an oil.

(e) Synthesis oftrans-7-[3-(1-adamantyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid:

813 mg (2 mmol) of the ester obtained in step (d) above and 50 ml ofmethanol were introduced into a round-bottomed flask sheltered from thelight and under a stream of nitrogen. 2.5 ml (10 mmol) of sodiumhydroxide (4N) were added dropwise and the mixture was heated to refluxfor two hours. After cooling, ethyl acetate was added and the mixturewas acidified with hydrochloric acid (4N), and the organic phase wasseparated out after settling of the phases had taken place, washed withwater, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of THF and hexane (30/70). Afterevaporation of the solvents, 400 mg of7-[3-(1-adamantyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 210° C. with decomposition, were collected(yield: 53%).

EXAMPLE 2 Preparation of ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate

831 mg (2 mmol) of the ester obtained in Example 1(d) and 30 ml of THFwere introduced not actually applied). Into a round-bottomed flask undera stream of nitrogen. 60 mg (2 mmol) of sodium hydride (80% in oil) wereadded portionwise and the mixture was stirred until the evolution of gasceased. 125 μl (2 mmol) of methyl iodide were then added and the mixturewas stirred at room temperature for three hours. The reaction medium waspoured into water and extracted with ethyl ether, and the organic phasewas separated out after settling of the phases had taken place, driedover magnesium sulfate and evaporated.

The residue obtained was purified on a column of silica eluted with amixture of dichloromethane and hexane (50/50). 714 mg of the expectedester were collected (yield: 85%) in the form of an oil.

EXAMPLE 3 Preparation oftrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

(a) Synthesis of 2-[3-(1-adamantyl)-4-methoxyphenyl]-3-buten-2-ol:

In a manner similar to that of Example 1(a), starting with 12.7 g (44.6mmol) of 3-(1-adamantyl)-4-methoxyacetophenone and after chromatographyon a column of silica eluted with a mixture of ethyl acetate and hexane(10/90), 7.6 g of the expected alcohol were obtained (yield: 54%) in theform of a yellow oil.

(b) Synthesis of3-[3-(1-adamantyl)-4-methoxyphenyl]-2-butene-sulfonylbenzene:

In a manner similar to that of Example 1(b), starting with 7.6 g (24.2mmol) of the alcohol obtained in step (a) above and after chromatographyon a column of silica eluted with a mixture of ethyl acetate and hexane(15/85), 5.2 g of the expected compound were obtained (yield: 49%).

(c) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-5-benzenesulfonyl-3,7-dimethyl-2,6-heptadienoate:

In a manner similar to that of Example 1(c), starting with 5.18 g (11.9mmol) of 3-[3-(1-adamantyl)-4-methoxyphenyl]-2-butenesulfonylbenzeneobtained in step (b) above and after chromatography on a column ofsilica eluted with a mixture of ethyl acetate and hexane (20/80), 5 g(75%) of the expected ester were obtained.

(d) Synthesis oftrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid:

4.6 g (8.2 mmol) of the ester prepared in step (c) above and 50 ml ofmethanol wee introduced into a round-bottomed flask sheltered from thelight and under a stream of nitrogen. 23 ml (98 mmol) of methanolicpotassium hydroxide (4N) wee then added dropwise and the mixture washeated to reflux for two hours. After cooling, ethyl ether and waterwere added and the mixture was acidified with sulfuric acid (4N), andthe organic phase was separated out after settling of the phases hadtaken place, washed with water, dried over magnesium sulfate andevaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and dichloromethane(15/85). After evaporation of the solvents, 2.3 g oftrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 212° C. with decomposition, were collected(yield: 72%).

EXAMPLE 4 Preparation of(2Z,4E,6E)-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

In the reaction of Example 3 (d), during the chromatography on silicaeluted with a mixture of ethyl acetate and dichloromethane (15/85), 310mg of(2Z,4E,6E)-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 207° C. with decomposition, were alsoobtained (yield: 9%).

EXAMPLE 5 Preparation oftrans-5-[7-(1-adamantyl)-6-methoxyethoxy-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid

(a) Synthesis of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene:

22.3 g (0.1 mmol) of 6-bromo-2-naphthol, 15.2 g (0.1 mol) of1-adamantanol and 100 ml of dichloromethane were introduced into around-bottomed flask. 5.5 ml of concentrated hydrochloric acid wereadded and the mixture was stirred at room temperature for twelve hours.The mixture was evaporated to dryness and the residue was taken up inwater and neutralized with sodium bicarbonate. The resulting mixture wasextracted with ethyl acetate and the organic phase was separated outafter settling of the phases had taken place, dried over magnesiumsulfate and evaporated.

The residue obtained was triturated in a mixture of dichloromethane andheptane (30/70), filtered and dried. 19 g (53%) of the expectedcompound, with a melting point of 215-6° C., were collected.

(b) Synthesis of 7-(1-adamantyl)-6-methoxyethoxy-2-bromonaphthalene:

17.85 g (50 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene and200 ml of DMF were introduced into a three-necked flask under a streamof nitrogen. 1.8 g (50 mmol) of sodium hydride (80% in oil) wereintroduced portionwise and the mixture was stirred at room temperatureuntil the evolution of gas ceased. The mixture was cooled to 5° C. and6.9 ml (60 mmol) of methoxyethoxymethyl chloride were introduceddropwise, and was stirred for two hours. The reaction medium was pouredinto ice-water and extracted with ethyl ether, and the organic phase wasseparated out after settling of the phases had taken place, dried overmagnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of dichloromethane and heptane (40/60).After evaporation of the solvents, 19.5 g (87%) of the expectedcompound, with a melting point of 99°-100° C., were collected.

(c) Synthesis of7-(1-adamantyl)-6methoxyethoxymethoxy-2-naphthalenecarboxaldehyde:

15 g (33.7 mmol) of7-(1-adamantyl)-6-methoxyethoxymethoxy-2-bromonaphthalene and 150 ml ofTHF were introduced into a three-necked flask under a stream ofnitrogen. A solution of 14.9 ml of n-butyllithium (2.5M in hexane) wasadded dropwise at −78° C. and the mixture was stirred for one hour. Atthis same temperature, 3.1 ml (40.4 mmol) of DMF were added and themixture was permitted to return to room temperature. The reaction mediumwas poured into saturated aqueous ammonium chloride solution andextracted with ethyl ether, and the organic phase was separated outafter settling of the phases had taken place, dried over magnesiumsulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and heptane (1/4). Afterevaporation of the solvents, 7.7 g (57%) of the expected aldehydederivative, with a melting point of 115°-6° C., were collected.

(d) Synthesis of ethyltrans-5-[7-(1-adamantyl)-6-methoxyetyoxy-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoate:

3.1 ml (22.2 mol) of diisopropylamine, 40 ml of HMPA and 60 ml of THFwere introduced into a three-necked flask under a stream of nitrogen.8.9 ml of n-butyllithium (2.5M in hexane) were introduced dropwise at 0°C. and the mixture was stirred for 30 min. A solution of 6.3 ml (20.7mmol) of triethyl 3-methyl-4-phosphonocrotonate in 50 ml of THF wasadded dropwise at −60° C., and the mixture was stirred for one hour,followed by dropwise addition of a solution of 6 g (14.8 mmol) of7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthalenecarboxaldehydedissolved in 30 ml of THF, and the mixture was permitted to return toroom temperature. The reaction medium was poured into saturated aqueousammonium chloride solution and extracted with ethyl ether, and theorganic phase was separated out after settling of the phases had takenplace, dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and heptane (1/9). Afterevaporation of the solvents, 6 g (85%) of the expected ethyl ester werecollected in the form of a yellow oil.

(c) Synthesis oftrans-5-[-7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid:

In a manner similar to that of Example 1(e), starting with 1.2 g (2.5mmol) of the above ethyl ester, 350 mg (35%) oftrans-5-[-7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid, with a melting point of 195°-6° C., were obtained.

EXAMPLE 6 Preparation of trans5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4pentadienoic acid

(a) Synthesis of ethyltrans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoate:

5.6 g (11.8 mmol) of ethyltrans-5-[-7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-3-methyl-2,4-pentadienoateand 60 ml of dichloromethane were introduced into a three-necked flaskunder a stream of nitrogen. 13 ml of boron trichloride (1M indichloromethane) were added dropwise at −70° C. and the mixture waspermitted to return to room temperature. The reaction medium was pouredinto ice-water and extracted with ethyl ether, and the organic phase wasseparated out after settling of the phases had taken place, dried overmagnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of ethyl acetate and heptane (1/4). Afterevaporation of the solvents, 1.4 g (85%) of the expected ethyl ester,with a melting point of 212°-4° C., were collected.

(b) Synthesis oftrans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid:

In a manner similar to that of Example 1(e), starting with 1.3 g (3.1mmol) of the above ethyl ester, 320 mg (25%) oftrans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid, with a melting point of 240°-5° C., were obtained.

EXAMPLE 7 Preparation oftrans-5-[-7-(1-adamantyl)-6-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid

(a) Synthesis of ethyltrans-5-[-7-(1-adamantyl)-6-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoate:

In a manner similar to that of Example 2, by reaction of 1.4 g (3.3mmol) of the ethyltrans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoatewith 260 μl (4 mmol) of methyl iodide, 330 mg (80%) of the expectedethyl ester were obtained.

(b) Synthesis oftrans-5-[-7-(1-adamantyl)-6-methoxy-2-naphthyl]3-methyl-2,4-pentadienoicacid:

In a manner similar to that of Example 1(e), starting with 1.1 g (2.7mmol) of the above ethyl ester, 478 mg (43%) oftrans-5-[-7-(1-adamantyl)-6-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid, with a melting point of 290°-1° C., were obtained.

EXAMPLE 8 Preparation oftrans-5-[7-(1-adamantyl)-6-propyloxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid

(a) Synthesis of ethyltrans-5-[-7-(1-adamantyl)-6-proploxy-2-naphthyl]-3-methyl-2,4-pentadienoate:

In a manner similar to that of Example 2, by reaction of 1.4 g (3.3mmol) of the ethyltrans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoatewith 400 μl (4 mmol) of 3-iodopropane, 1.12 g (75%) of the expectedethyl ester, with a melting point of 133°-4° C., were obtained.

(b) Synthesis oftrans-5-[-7-(1-adamantyl)-6-proploxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid:

In a manner similar to that of Example 1(e), starting with 1.1 g (2.4mmol) of the above ethyl ester, 770 mg (80%) oftrans-5-[-7-(1-adamantyl)-6-propyloxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid, with a melting point of 240°-1° C., were obtained.

EXAMPLE 9 Preparation oftrans-7-[3-(1-methylcyclohexyl)-4-hydroxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

(a) Synthesis of 3-(1-methylcyclohexyl)-4-methoxyphenylethanone:

4.6 g (1.85 mmol) of 3-(1-methylcyclohexyl)-4-methoxybenzoic acid and 50ml of THF were introduced into a three-necked flask under a stream ofnitrogen. 29 ml (4.6 mmol) of methyllithium (1.6M in ethyl ether) wereadded dropwise at −30° C. and the mixture was permitted to return toroom temperature. The reaction medium was poured into ice-water andextracted with ethyl acetate, and the organic phase was separated outafter settling of the phases had taken place, dried over magnesiumsulfate and evaporated.

4.6 g (99%) of the expected ketone derivative were collected in the formof a colorless oil.

(b) Synthesis of3-methyl-3-[3-(1-methylcyclohexyl)-4-methoxyphenyl]acrylonitrile:

4.5 g (18.3 mmol) of compound (a) were dissolved in 50 ml of THF and 3.2g (27 mmol) of diethyl cyanomethylphosphonate and 2.4 g of groundpotassium hydroxide were then successively added. The mixture wasstirred at room temperature for four hours. The reaction medium waspoured into ice-water and extracted with ethyl acetate, and the organicphase was separated out after settling of the phases had taken place,dried over magnesium sulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of dichloromethane and heptane (50/50);2.86 g (58%) of the expected nitrile were collected.

(c) Synthesis of3-[3-(1-methylcyclohexyl)-4-methoxyphenyl]crotonaldehyde:

2.8 g (10.4 mmol) of the above aldehyde were dissolved in 50 ml ofanhydrous toluene, and 13 ml (13 mmol) of diisobutylaluminum hydridesolution (1M in toluene) were added dropwise at −70° C. The mixture waspermitted to return to 0° C. and was stirred for 30 minutes. Dilutehydrochloric acid was added slowly and the mixture was then filteredover Celite. The filtrate was washed with water, dried over magnesiumsulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of dichloromethane and heptane (70/30).2.34 g (83%) of the expected aldehyde were collected.

(d) Synthesis of ethyltrans-7-[3-(1-methylcyclohexyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate:

In a manner similar to that of Example 5(d), by reaction of 2.3 g (8.6mmol) of 3-[3-(1-methylcyclohexyl)-4-methoxyphenyl]crotonaldehyde with4.4 ml (12.8 mmol) of triethyl 3-methyl-4-phosphono-2-butenoate, 2.13 g(65%) of the expected ethyl ester were obtained in the form of a yellowoil.

(e) Synthesis oftrans-7-[3-(1-methylcyclohexyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid:

In a manner similar to that of Example 1(e), starting with 2.13 g (5.5mmol) of the above ethyl ester and after chromatography on a column ofsilica eluted with dichloromethane, 540 mg (27%) oftrans-7-[3-(1-methylcyclohexyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 175°-7° C., were obtained.

EXAMPLE 10 Preparation of(2Z,4E,6E)-7-[3-(1-methylcyclohexyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

In the reaction of Example 9(e), during the chromatography on a columnof silica eluted with dichloromethane, 100 mg (5%) of(2Z,4E,6E)-7-[3-(1-methylcyclohexyl)-4-methylphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 165°-167° C., were obtained.

EXAMPLE 11 Preparation oftrans-7-[3-(1-adamantyl)-4-isopropyloxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

(a) Synthesis of 3-(1-adamantyl)-4-isopropyloxyphenylethanone:

In a manner similar to that of Example 9(a), by reaction of 5 g (16mmol) of 3-(1-adamantyl)-4-isopropyloxybenzoic acid with 25 ml (44 mmol)of methyllithium (1.6M), 4.9 g (98%) of the expected ketone derivative,with a melting point of 101°-2° C., were obtained.

(b) Synthesis of3-methyl-3-[3-(1-adamantyl)-4-isopropyloxyphenyl]-acrylonitrile:

In a manner similar to that of Example 9(b), by reaction of 3.6 g (11.5mmol) of the above ketone with 2.03 g (17.3 mmol) of diethylcyanomethylphosphonate, 2.07 g (54%) of expected nitrile were obtained.

(c) Synthesis of 3-[3-(1-adamantyl)-4-isopropyloxyphenyl]crotonaldehyde:

In a manner similar to that of Example 9(c), starting with 3.1 g (9.2mmol) of the above nitrile, 2.28 g (73%) of the expected aldehyde wereobtained.

(d) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-isopropyloxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate:

In a manner similar to that of Example 5(d), by reaction of 1.37 g (4mmol) of 3-[3-(1-adamantyl)-4-isopropyloxyphenyl]crotonaldehyde with1.92 ml (6 mmol) of triethyl 3-methyl-4-phosphono-2-butenoate, 1 g (57%)of the expected ethyl ester were obtained in the form of a yellow oil.

(e) Synthesis oftrans-7-[3-(1-adamantyl)-4-isopropyloxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid:

In a manner similar to that of Example 1(e), starting with 1.7 g (3.7mmol) of the above ethyl ester and after chromatography on a column ofsilica eluted with dichloromethane, 800 mg (50%) of7-[3-(1-adamantyl)-4-isopropyloxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 209°-10° C., were obtained.

EXAMPLE 12 Preparation oftrans-7-[3-(1-adamantyl)-4-methoxypethoxy-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid

(a) Synthesis of 3-(1-adamantyl)-4-methoxyethoxymethoxphenylethanone:

In a manner similar to that of Example 9(a), by reaction of 17 g (47mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid with 73 ml(118 mmol) of methyllithium (1.6M), 18 g (100%) of the expected ketonederivative were obtained in the form of a yellow oil.

(b) Synthesis of3-methyl-3-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]acrylonitrile:

In a manner similar to that of Example 9(b), by reaction of 5 g (14mmol) of the above ketone with 3.4 ml (21 mmol) of diethylcyanomethylphosphonate, 5.8 g (100% of expected nitrile were obtained inthe form of a yellow oil.

(c) Synthesis of3-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]-crotonaldehyde:

In a manner similar to that of Example 9(c), starting with 5.3 g (13.9mmol) of the above nitrile, 2.4 g (100%) of the expected aldehyde, witha melting point of 80° C., were obtained.

(d) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate:

In a manner similar to that of Example 5(d), by reaction of 1.9 g (4.9mmol) of 3-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]crotonaldehydewith 2 ml (7.3 mmol) of triethyl 3-methyl-4-phosphono-2-butenoate, 2 g(82%) of the expected ethyl ester, with a melting point of 83°-5° C.were obtained.

(e) Synthesis oftrans-7-[3-(1-adamantyl)-4-methoxyethoxymethoxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid:

In a manner similar to that of Example 1(e), starting with 2 g (4 mmol)of the above ethyl ester and after chromatography on a column of silicaeluted with a mixture of ethyl acetate and dichloromethane (10/90), 710mg (38%) oftrans-7-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 170°-2° C., were obtained.

EXAMPLE 13 Preparation of ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoate

(a) Synthesis of3-methyl-3-[3-(1-adamantyl)-4-methoxyphenyl]-acrylonitrile:

In a manner similar to that of Example 9(b), by reaction of 5 g (17.6mmol) of 3-(1-adamantyl)-4-methoxyphenylethanone with 8.4 ml (52.8 mmol)of diethyl cyanomethylphosphonate, 3.8 g (70%) of expected nitrile, witha melting point of 163°-5° C., were obtained.

(b) Synthesis of 3-[3-(1-adamantyl)-4-methoxyphenyl]crotonaldehyde:

In a manner similar to that of Example 9(c), starting with 7 g (22.8mmol) of the above nitrile, 4.8 g (68%) of the expected aldehyde, with amelting point of 163°-5° C., were obtained.

(c) Synthesis of ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoate:

In a manner similar to that of Example 5(d), by reaction of 500 mg (1.6mmol) of 3-[3-(1-adamantyl)-4-methoxyphenyl]crotonaldehyde with 550 μl(2.4 mmol) of triethyl trans-4-phosphono-2-butenoate, 540 mg (82%) ofthe expected ethyl ester, with a melting point of 143°-5° C., wereobtained.

(d) Synthesis oftrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoicacid:

In a manner similar to that of Example 1(e), starting with 540 mg (1.3mmol) of the above ethyl ester and after chromatography on a column ofsilica eluted with a mixture of ethyl acetate and dichloromethane(5/95), 220 mg (45%) of7-[3-(1-adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoic acidwere obtained.

EXAMPLE 14 Preparation of ethyltrans-7-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoate

(a) Synthesis of3-tert-butyl-4-methoxyethoxymethoxyphenyl)-1-bromobenzene:

2.4 g (81 mmol) of sodium hydride (80% in oil) and 50 ml of DMF wereintroduced into a three-necked flask under a stream of nitrogen, and asolution of 17.6 g (77 mmol) of 2-tert-butyl-4-bromophenol in 100 ml ofDMF was added dropwise and the mixture was stirred until the evolutionof gas ceased. A solution of 10.5 ml (92 mmol) of 2-methoxyethoxymethylchloride in 20 ml of DMF was then added dropwise and the mixture wasstirred for four hours at room temperature. The reaction medium waspoured into water and extracted with ethyl ether, and the organic phasewas separated out after settling of the phases had taken place, washedwith water, dried over magnesium sulfate and evaporated.

The residue was purified by chromatography on a column of silica elutedwith a mixture of dichloromethane and hexane (50/50). After evaporationof the solvents, 21.4 g (88%) of the expected compound were collected inthe form of a light brown oil.

(b) Synthesis of 3-tert-butyl-4-methoxyethoxymethoxybenzoic acid:

21.4 g (68 mmol) of the above compound were dissolved in 200 ml of THF,and a solution of 30 ml of n-butyllithium (2.5M in hexane) was addeddropwise at −78° C. under a stream or nitrogen, and the mixture wasstirred for 30 minutes. A stream of CO₂ was passed therethrough for onehour at −78° C. and the reaction medium was permitted to return to roomtemperature and poured into saturated aqueous ammonium chloride solutionand extracted with ethyl ether, and the organic phase was separated outafter settling of the phases had taken place, dried over magnesiumsulfate and evaporated.

The residue obtained was purified by chromatography on a column ofsilica eluted with a mixture of dichloromethane. 11 g (58%) of theexpected acid were collected.

(c) Synthesis of 3-tert-butyl-4-methoxyethoxymethoxyphenylethanone:

In a manner similar to that of Example 9(a), by reaction of 11 g (39mmol) of 3-tert-butyl-4-methoxyethoxymethoxybenzoic acid with 49 ml (78mmol) of methyllithium (1.6M), 8.5 g (75%) of the expected ketonederivative were obtained in the form of yellow oil.

(d) Synthesis of3-methyl-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)acrylonitrile:

In a manner similar to that of Example 9(b), by reaction of 8.5 g (30mmol) of the above ketone with 14.3 ml (90 mmol) of diethylcyanomethylphosphonate, 7 g (76%) of expected nitrile were obtained inthe form of a yellow oil.

(e) Synthesis of3-(3-tert-butyl-4-methoxyethoxymethocyphenyl)-crotonaldehyde:

In a manner similar to that of Example 9(c), starting with 7 g (23 mmol)of the above nitrile, 6 g (85%) of the expected aldehyde were obtainedin the form of yellow oil.

(f) Synthesis of ethlytrans-7-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoate;

In a manner similar to that of Example 5(d), by reaction of 6 g (19.6mmol) of 3-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)crotonaldehydewith 8.1 ml (29.4 mmol) of triethyl 3-methyl-4-phosphono-2-butenoate,6.6 g (81%) of the expected ethyl ester were obtained in the form of ayellow oil.

(g) Synthesis oftrans-7-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoicacid:

In a manner similar to that of Example 1(e), starting with 1.1 g (2.6mmol) of the above ethyl ester and after recrystallization in a mixtureof dichloromethane and heptane, 320 mg (32%) oftrans-7-(3-tert-butyl-4-methoxyethoxymethoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoicacid, with a melting point of 147°-8° C., were obtained.

EXAMPLE 15

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

(A) Oral Route: (a) 0.2 g Tablet: (i) Compound prepared in Example 30.001 g (ii) Starch 0.114 g (iii) Dicalcium phosphate 0.020 g (iv)Silica 0.020 g (v) Lactose 0.030 g (vi) Talc 0.010 g (vii) Magnesiumstearate 0.005 g (b) Oral (drinkable) suspension in 10 ml ampoules: (i)Compound of Example 3 0.05 g (ii) Glycerol 1.000 g (iii) 70% Sorbitol1.000 g (iv) Sodium saccharinate 0.010 g (v) Methyl para-hydroxybenzoate0.080 g (vi) Flavoring qs (vii) Purified water qs 10 ml (B) TOPICALROUTE: (a) Ointment: (i) Compound of Example 3 0.020 g (ii) Isopropylmyristate 81.700 g (iii) Liquid petrolatum 9.100 g (iv) Silica (“Aerosil200” 9.180 g marketed by Degussa) (b) Ointment: (i) Compound of Example3 0.300 g (ii) White petrolatum codex qs 100 g (c) Nonionic water-in-oilcream: (i) Compound of Example 3 0.100 g (ii) Mixture of oils, waxes and39.900 g emulsified lanolin alcohols (“Anhydrous Eucerine” marketed byBDF) (iii) Methyl para-hydroxybenzoate 0.075 g (iv) Propylpara-hydroxybenzoate 0.075 g (v) Sterile demineralized water qs 100 g(d) Lotion: (i) Compound of Example 3 0.100 g (ii) Polyethylene glycol(PEG 400) 69.900 g (iii) 95% Ethanol 30.000 g (e) Hydrophobic ointment:(i) Compound of Example 3 0.300 g (ii) Isopropyl myristate 36.400 g(iii) Silicone oil (“Rhodonsil 47 V 36.400 g 300” marketed byRhone-Poulenc) (iv) Beeswax 13.600 g (v) Silicone oil (“Abil 300,000cat” qs 100 g marketed by Goldschmidt) (f) Nonionic oil-in-water cream:(i) Compound of Example 3 0.500 g (ii) Cetyl alcohol 4.000 g (iii)Glyceryl monostearate 2.500 g (iv) PEG 50 stearate 2.500 g (v) Karitebutter 9.200 g (vi) Propylene glycol 2.000 g (vii) MethylPara-hydroxybenzoate 0.075 g (viii) Propyl Para-hydroxybenzoate 0.075 g(ix) Sterile demineralized water qs 100 g

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. An aromatic polenic polyenic compound having thestructural formula (I):

in which R₁ is a —CH₃ radical, a radical —CH₂—O—R₉, a radical—CH₂—O—CO—R₁₀, or a radical —CO—R₁₁, wherein R₉, R₁₀, and R₁₁ are asdefined below; R₂ is a hydrogen atom or a lower alkyl radical having 1to 6 carbon atoms; R₃ is a hydrogen atom or a lower alkyl radical having1 to 6 carbon atoms; R₅ is a hydrogen atom or a lower alkyl radicalhaving 1 to 6 carbon atoms; R₇ and R₈ independently are each (i) ahydrogen atom, (ii) a linear or branched alkyl radical having from 1 to20 carbon atoms, (iii) a cycloaliphatic radical selected from the groupconsisting of 1-methylcyclohexyl and 1-adamantyl, (iv) a radical—O—CH₂—O—CH₂—CH₂—O—CH₃, (v) a radical —O—R₁₃, or (vi) a radical—S(O)_(n)R₁₃, wherein R₁₃ and n are as defined below, R₄ and R₆ togetherform, with the carbon atoms from which they depend and with the adjacentbenzene ring, a naphthalene ring, and at least one of R₇ and R₈ has theabove definition (ii) or (iii); R₉ is a hydrogen atom or a lower alkylradical having 1 to 6 carbon atoms; R₁₀ is a lower alkyl radical having1 to 6 carbon atoms; R₁₁ is (a) a hydrogen atom, (b) a lower alkylradical having 1 to 6 carbon atoms, (c) a radical of formula:

in which R′ and R″ independently are each a hydrogen atom, a lower alkylradical having 1 to 6 carbon atoms, a mono- or polyhydroxyalkyl radicalrespectively having 2 to 3 carbon atoms or 3 to 6 carbon atomscontaining 2 to 5 hydroxyl groups, or an optionally substituted phenylradical which if substituted, is substituted with at least one halogenatom, hydroxyl or nitro group, or (d) a radical —OR₁₂, wherein R₁₂ is ahydrogen atom, a linear or branched alkyl radical having from 1 to 20carbon atoms, an alkenyl radical having 2 to 5 carbon atoms and at leastone site of ethylenic unsaturation, a mono- or polyhydroxyalkyl radicalrespectively having 2 to 3 carbon atoms or 3 to 6 carbon atoms and 2 to5 hydroxyl groups, or an optionally substituted phenyl or radical benzylradical or pheneyl phenyl radical wherein, if substituted, aresubstituted by at least one halogen atom, hydroxyl or nitro functionalgroup; R₁₃ is a hydrogen atom or a linear or branched alkyl radicalhaving from 1 to 20 carbon atoms; and n is an integer equal to 0, 1 or2; or a pharmaceutically/cosmetically acceptable salt or optical orgeometric isomer thereof.
 2. An aromatic polyenic compound as defined byclaim 1, comprising a pharmaceutically acceptable salt thereof.
 3. Anaromatic polyenic compound as defined by claim 1, wherein formula (I),the lower alkyl radical substituents are selected from the groupconsisting of methyl, ethyl, isopropyl, butyl, tert-butyl and hexylradicals.
 4. An aromatic polyenic compound as defined by claim 1,wherein formula (I), the linear or branched alkyl radical substituentshaving from 1 to 20 carbon atoms are selected from the group consistingof methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl andoctadecyl radicals.
 5. An aromatic polyenic compound as defied by claim1, wherein formula (I), the monohydroxyalkyl radical substituents areselected from the group consisting of 2-hydroxypropyl and3-hydroxypropyl radicals.
 6. An aromatic polyenic compound as defined byclaim 1, wherein formula (I), the polyhydroxyalkyl radical substituentsare selected from the group consisting of 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl and pentaerythritolradicals.
 7. An aromatic polyenic compound selected from the groupconsisting oftrans-7-[3-(1-adamantyl)-4-hydroxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid; ethyltrans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate;trans-7-[-3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;(2Z,4E,6E)-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;trans-5-[-7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-3-methyl-2,4,-pentadienoicacid;trans-5-[-7-(1-adamantyl)-6-hydroxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;trans-5-[-7-(1-adamantyl)-6-methoxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;trans-5-[-7-(1-adamantyl)-6-propyloxy-2-naphthyl]-3-methyl-2,4-pentadienoicacid;trans-7-[3-(1-methylcyclohexyl)-4-hydroxy-phenyl]-3,7-dimethyl]-2,4,6-heptatrienoicacid;(2Z,4E,6E)-7-[3-(1-methylcyclohexyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;trans-7-[3-(1-adamantyl)-4-isopropyloxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;trans-7-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid;trans-7-[3-(1-adamantyl)-4-methoxyphenyl]-7-methyl-2,4,6-heptatrienoicacid;trans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrien-1-ol;trans-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrien-1-al;trans-N-ethyl-7-[3-(1-adamantyl)-4-methoxy-phenyl]-3,7-dimethyl-2,4,6-heptatrienecarboxamide;trans-N-4-hydroxphenyl-7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienecarboxamide;trans-7-(3-tert-butyl-4-methoxyethoxymethoxy-phenyl)-3,7-dimethyl-2,4,6-heptatrienoicacid; ethyltrans-7-(3-tert-butyl-4-hydroxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoate;ethyltrans-7-(3-tert-butyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoate;and ethyltrans-7-[4-(1-adamantyl)-3-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoate.8. An aromatic polyenic compound as defined by claim 2, which is analkali or alkaline earth metal, zinc or amine salt.
 9. An aromaticpolyenic compound as defined by claim 1, wherein formula (I), at leastone of the following definitions exist: R₁ is a radical —CO—R₁₁; or R₇is the adamantyl radical.
 10. A pharmaceutical composition of matter,comprising a therapeutically effective amount of an aromatic polyeniccompound as defined by claim 1, or pharmaceutically acceptable salt orisomer thereof, and a pharmaceutically acceptable vehicle, carrier ordiluent therefor.
 11. The pharmaceutical composition as defined by claim10, further comprising a retinoid compound, a D vitamin, acorticosteroid, an anti-free radical agent, an α-hydroxy or α-keto acidas ion channel blocker, or combination thereof.
 12. The pharmaceuticalcomposition as defined by claim 10, selected from the group consistingof a tablet, a capsule, a syrup, a dragee, a suspension, an elixir, asolution, a powder, granules, an emulsion , microspheres, nanospheres,lipid vesicles, polymeric vesicles, and a composition for injection. 13.The pharmaceutical composition as defined by claim 10, selected from thegroup consisting of an ointment, a cream, a milk, a salve, animpregnated pad, a gel, a spray, or a lotion.
 14. The pharmaceuticalcomposition as defined by claim 10, for topical administration.
 15. Thepharmaceutical composition as defined by claim 10, for systemicadministration.
 16. The pharmaceutical composition as defined by claim10, comprising from 0.001% to 5% by weight of said aromatic polyeniccompound, or salt or isomer thereof.
 17. A cosmetic composition ofmatter, comprising a cosmetically effective amount of an aromaticpolyenic compound as defined by claim 1, or cosmetically acceptable saltor isomer thereof, and a commercially acceptable vehicle, carrier ordiluent therefor.
 18. The cosmetic composition as defined by claim 17,which is selected from the group consisting of a cream, a milk, alotion, a gel, an ointment, microspheres, nanospheres, lipid vesicles,polymeric vesicles, a soap, and a shampoo.
 19. The cosmetic compositionas defined by claim 17, comprising from 0.001% to 3% by weight of saidaromatic polyenic compound, or salt or isomer thereof.
 20. The cosmeticcomposition as defined by claim 17, further comprising a compoundselected from the group consisting of retinoid compound, a D vitamin acorticosteroid, an anti-free radical agent, an α-hydroxy or α-keto acidan ion channel blocker, and combinations thereof.
 21. The pharmaceuticalcomposition as defined by claim 10, further comprising a compoundselected from the group consisting of a wetting agent, a depigmentingagent, a moisturizing agent, an emollient, an antiseborrhoeic oranti-acne agent, an antibiotic, an antifungal agent, a hair regrowthpromoter, a non-steroidal anti-inflammatory agent, a carotenoid, ananti-psoriatic agent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoicacid or ester or amide thereof, and combinations thereof.
 22. Thepharmaceutical composition as defined by claim 10, further comprising acompound selected from the group consisting of a taste- orflavor-enhancing agent, a preservative, a stabilizer, a moistureregulating agent, a pH regulating agent, an osmotic pressure modifyingagent, an emulsifying agent, a UV-A or UV-B screening agent, anantioxidant, and combinations thereof.
 23. The cosmetic composition byclaim 17, further comprising a compound selected from the groupconsisting of a wetting agent, a depigmenting agent, a moisturizinggent, an emollient, an antiseborrhoeic or antiacne agent, an antibiotic,an antifungal agent, a hair regrowth promoter, a non-steroidalanti-inflammatory agent, a carotenoid, an anti-psoriatic agent,5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or ester oramide thereof, and combinations thereof.
 24. The cosmetic composition asdefined by claim 17 further comprising a compound selected from thegroup consisting of a taste- or flavor-enhancing agent, a preservative,a stabilizer, a moisture regulating agent, a pH regulating agent, anosmotic pressure modifying agent, an emulsifying agent, a UV-A or UV-Bscreening agent, an antioxidant, and combinations thereof.
 25. Anaromatic polyenic compound having the structural formula (I):

in which R ₁ is a —CH ₃ radical, a radical —CH ₂ —O—R ₉ , a radical —CH₂ —O—CO—R ₁₀ , or a radical —CO—R ₁₁ , wherein R ₉ , R ₁₀ , and R ₁₁ areas defined below; R ₂ is a hydrogen atom or a lower alkyl radical; R ₃is a hydrogen atom or a lower alkyl radical; R ₄ is a hydrogen atom; R₅is a hydrogen atom or a lower alkyl radical; R ₆ is a hydrogen atom, alinear or branched alkyl radical having from 1 to 20 carbon atoms, aradical —O—CH ₂ —O—CH ₂ —CH ₂ —O—C ₃ or a radical —O—R ₁₃ , wherein R ₁₃is as defined below; R ₇ and R ₈ independently are each (i) a hydrogenatom, (ii) a linear or branched alkyl radical having from 1 to 20 carbonatoms, (iii) a cycloaliphatic radical, (iv) a radical —O—CH ₂ —O—CH ₂—CH ₂ —O—CH ₃ , (v) a radical —O—R ₁₃ , or (vi) a radical —S(O)_(n) R ₁₃, wherein R ₁₃ and n are as defined below, and at least one of R ₇ and R₈ has the above definition (ii) or (iii); R ₉ is a hydrogen atom or alower alkyl radical; R ₁₀ is a lower alkyl radical; R ₁₁ is (a) ahydrogen atom, (b) a lower alkyl radical, or (c) a radical of formula:

in which R′ and R″ independently are each a hydrogen atom, a lower alkylradical, a mono- or polyhydroxyalkyl radical, or an optionallysubstituted phenyl radical, or (d) a radical —OR ₁₂ , wherein R ₁₂ is ahydrogen atom, a linear or branched alkyl radical having from 1 to 20carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical,or an optionally substituted aryl or aralkyl radical; R ₁₃ is a hydrogenatom or a linear or branched alkyl radical having from 1 to 20 carbonatoms; and n is an integer equal to 0, 1 or 2; or apharmaceutically/cosmetically acceptable salt or optical or geometricisomer thereof.
 26. An aromatic polyenic compound as defined by claim25, comprising a pharmaceutically acceptable salt thereof.
 27. Anaromatic polyenic compound as defined by claim 25, where in formula (I),the lower alkyl radical substituents are selected from the groupconsisting of methyl, ethyl, isopropyl, butyl, tert-butyl and hexylradicals.
 28. An aromatic polyenic compound as defined by claim 25,where in formula (I), the linear or branched alkyl radical substituentshaving from 1 to 20 carbon atoms are selected from the group consistingof methyl, ethyl, propyl, 2 -ethylhexyl, octyl, dodecyl, hexadecyl andoctadecyl radicals.
 29. An aromatic polyenic compound as defined byclaim 25, where in formula (I), the monohydroxyalkyl radicalsubstituents are selected from the group consisting of 2 -hydroxypropyland 3 -hydroxypropyl radicals.
 30. An aromatic polyenic compound asdefined by claim 25, where in formula (I), the polyhydroxyalkyl radicalsubstituents are selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4 -trihydroxybutyl, 2,3,4,5 -tetrahydroxypentyland pentaerythritol radicals.
 31. An aromatic polyenic compound asdefined by claim 25, where in formula (I), the aryl radical substituentsare selected from the group consisting of phenyl radicals optionallysubstituted by at least one halogen atom, or a hydroxyl or nitrofunctional group.
 32. An aromatic polyenic compound as defined by claim25, where in formula (I), the aralkyl radical substituents are selectedfrom the group consisting of benzyl and phenethyl radicals optionallysubstituted by at least one halogen atom, or a hydroxyl or nitrofunctional group.
 33. An aromatic polyenic compound as defined by claim25, wherein formula (I), the alkenyl radical substituents have from 2 to5 carbon atoms.
 34. An aromatic polyenic compound as defined by claim25, where in formula (I), the cycloaliphatic radical substituents areselected from the group consisting of 1 -methylcyclohexyl and 1-adamantyl radicals.
 35. An aromatic polyenic compound as defined byclaim 26, which in selected from the group consisting of an alkali oralkaline earth metal, zinc or amine salt.
 36. An aromatic polyeniccompound as defined by claim 25, where in formula (I), at least one ofthe following definitions is satisfied: R ₁ is a radical —CO—R ₁₁ ; R ₇is the adamantyl radical; and R ₆ is a hydrogen atom or a linear orbranched alkyl radical having from 1 to 20 carbon atoms.
 37. Apharmaceutical composition of matter, comprising a therapeuticallyeffective amount of an aromatic polyenic compound as defined by claim25, or pharmaceutically acceptable salt or isomer thereof, and apharmaceutically acceptable vehicle, carrier or diluent therefor. 38.The pharmaceutical composition as defined by claim 37, furthercomprising a compound selected from the group consisting of a retinoidcompound, a D vitamin, a corticosteroid, an anti-free radical agent, anα-hydroxy or α-keto acid, an ion channel blocker, and combinationsthereof.
 39. The pharmaceutical composition as defined by claim 37,which is in a pharmaceutically acceptable form selected from the groupconsisting of a tablet, a capsule, a syrup, a dragee, a suspension, anelixir, a solution, a powder, granule, an emulsion, microsphere,nanosphere, lipid vesicle, polymeric vesicle, and an injectablecomposition.
 40. The pharmaceutical composition as defined by claim 37,which is in a pharmaceutically acceptable form selected from the groupconsisting of an ointment, a cream, a milk, a salve, an impregnated pad,a gel, a spray, and a lotion.
 41. The pharmaceutical composition asdefined by claim 37, which is suitable for topical administration. 42.The pharmaceutical composition as defined by claim 37, which is suitablefor systemic administration.
 43. The pharmaceutical composition asdefined by claim 37, comprising from 0.001% to 5 % by weight of saidaromatic polyenic compound, or salt or isomer thereof.
 44. A cosmeticcomposition of matter, comprising a cosmetically effective amount of anaromatic polyenic compound as defined by claim 25, or cosmeticallyacceptable salt or isomer thereof, and a cosmetically acceptablevehicle, carrier or diluent therefor.
 45. The cosmetic composition asdefined by claim 44, which is in a cosmetically acceptable form selectedfrom the group consisting of a cream, a milk, a lotion, a gel, anointment, microsphere, nanosphere, lipid vesicle, polymeric vesicle, asoap, or a shampoo.
 46. The cosmetic composition as defined by claim 44,comprising from 0.001% to 3 % by weight of said aromatic polyeniccompound, or salt or isomer thereof.
 47. The cosmetic composition asdefined by claim 44, further comprising a compound selected from thegroup consisting of a retinoid compound, a D vitamin, a corticosteroid,an anti-free radical agent, an α-hydroxy or α-keto acid or derivativethereof, an ion channel blocker, and combinations thereof.
 48. Thepharmaceutical composition as defined by claim 37, further comprising anadditional compound selected from the group consisting of a wettingagent, a depigmenting agent, a moisturizing agent, an emollient, anantiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, ahair regrowth promoter, a non-steroidal anti-inflammatory agent, acarotenoid, an anti-psoriatic agent, 5,8,11,14 -eicosatetraynoic or5,8,11 -eicosatrynoic acid or ester or amide thereof, and combinationsthereof.
 49. The pharmaceutical composition as defined by claim 37,further comprising an additional compound selected from the groupconsisting of a taste- or flavor-enhancing agent, a preservative, astabilizer, a moisture regulating agent, a pH regulating agent, anosmotic pressure modifying agent, an emulsifying agent, a UV-A or UV-Bscreening agent, an antioxidant, and combinations thereof.
 50. Thecosmetic composition by claim 44, further comprising an additionalcompound selected from the group consisting of a wetting agent, adepigmenting agent, a moisturizing gent, an emollient, anantiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, ahair regrowth promoter, a non-steroidal anti-inflammatory agent, acarotenoid, an anti-psoriatic agent, 5,8,11,14 -eicosatetraynoic or5,8,11 -eicosatrynoic acid or an ester or an amide thereof, andcombinations thereof.
 51. The cosmetic composition as defined by claim44, further comprising an additional compound selected from the groupconsisting of a taste- or flavor-enhancing agent, a preservative, astabilizer, a moisture regulating agent, a pH regulating agent, anosmotic pressure modifying agent, an emulsifying agent, a UV-A or UV-Bscreening agent, an antioxidant, and combinations thereof.
 52. Thearomatic polyenic compound of claim 25, wherein R₆ is hydrogen.
 53. Thearomatic polyenic compound of claim 25, wherein R₆ is a linear orbranched alkyl radical having 1 to 20 carbon atoms.
 54. The aromaticpolyenic compound of claim 25, wherein R₆ is a radical —O—C ₂ —O—CH ₂—CH ₂ —O—CH ₃ .
 55. The aromatic polyenic compound of claim 25, whereinR₆ is an —O—R ₁₃ radical, wherein R ₁₃ is hydrogen or a linear orbranched alkyl radical having 1 to 20 carbon atoms.
 56. The aromaticpolyenic compound of claim 53, wherein said linear or branched alkylradical having 1 to 20 carbon atoms is selected from the groupconsisting of methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl,hexadecyl, and octadecyl radicals.
 57. The aromatic polyenic compound ofclaim 55, wherein R₁₃ is selected from the group consisting of methyl,ethyl, propyl, 2 -ethylhexyl, octyl, dodecyl, hexadecyl, and octadecylradicals.
 58. A pharmaceutical composition containing a pharmaceuticallyeffective amount of a compound according to claim 52, or apharmaceutically acceptable salt or isomer thereof, and apharmaceutically acceptable vehicle, carrier or diluent therefor.
 59. Apharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 53, or a pharmaceuticallyacceptable salt or isomer thereof, and a pharmaceutically acceptablevehicle, carrier or diluent therefor.
 60. A pharmaceutical compositioncontaining a pharmaceutically effective amount of a compound accordingto claim 54, or a pharmaceutically acceptable salt or isomer thereof,and a pharmaceutically acceptable vehicle, carrier or diluent therefor.61. A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 55, or a pharmaceuticallyacceptable salt or isomer thereof, and a pharmaceutically acceptablevehicle, carrier or diluent therefor.
 62. A pharmaceutical compositioncontaining a pharmaceutically effective amount of a compound accordingto claim 56, or a pharmaceutically acceptable salt or isomer thereof,and a pharmaceutically acceptable vehicle, carrier or diluent therefor.63. A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 57, or a pharmaceuticallyacceptable salt or isomer thereof, and a pharmaceutically acceptablevehicle, carrier or diluent therefor.
 64. A cosmetic compositioncontaining a cosmetically effective amount of a compound according toclaim 52, or a pharmaceutically acceptable salt or isomer thereof, and acosmetically acceptable vehicle, carrier or diluent therefor.
 65. Acosmetic composition containing a cosmetically effective amount of acompound according to claim 53, or a pharmaceutically acceptable salt orisomer thereof, and a cosmetically acceptable vehicle, carrier ordiluent therefor.
 66. A cosmetic composition containing a cosmeticallyeffective amount of a compound according to claim 54, or apharmaceutically acceptable salt or isomer thereof, and a cosmeticallyacceptable vehicle, carrier or diluent therefor.
 67. A cosmeticcomposition containing a cosmetically effective amount of a compoundaccording to claim 55, or a pharmaceutically acceptable salt or isomerthereof, and a cosmetically acceptable vehicle, carrier or diluenttherefor.
 68. A cosmetic composition containing a cosmetically effectiveamount of a compound according to claim 56, or a pharmaceuticallyacceptable salt or isomer thereof, and a cosmetically acceptablevehicle, carrier or diluent therefor.
 69. A cosmetic compositioncontaining a cosmetically effective amount of a compound according toclaim 57, or a pharmaceutically acceptable salt or isomer thereof, and acosmetically acceptable vehicle, carrier or diluent therefor.